First-in-human study of the epichaperome inhibitor PU-H71: clinical results and metabolic profile
- 275 Downloads
Background Molecular chaperone targeting has shown promise as a therapeutic approach in human cancers of various histologies and genetic backgrounds. The purine-scaffold inhibitor PU-H71 (NSC 750424), selective for Hsp90 in epichaperome networks, has demonstrated antitumor activity in multiple preclinical cancer models. The present study was a first in-human trial of PU-H71 aimed at establishing its safety and tolerability and characterizing its pharmacokinetic (PK) profile on a weekly administration schedule in human subjects with solid tumors refractory to standard treatments. Methods PU-H71 was administered intravenously over 1 h on days 1 and 8 of 21-day cycles in patients with refractory solid tumors. Dose escalation followed a modified accelerated design. Blood and urine were collected during cycles 1 and 2 for pharmacokinetics analysis. Results Seventeen patients were enrolled in this trial. Grade 2 and 3 adverse events were observed but no dose limiting toxicities occurred, thus the human maximum tolerated dose was not determined. The mean terminal half-life (T1/2) was 8.4 ± 3.6 h, with no dependency to dose level. A pathway for the metabolic disposal of PU-H71 in humans was derived from microsome studies. Fourteen patients were also evaluable for clinical response; 6 (35%) achieved a best response of stable disease for >2 cycles, with 2 patients remaining on study for 6 cycles. The study closed prematurely due to discontinuation of drug supply. Conclusions PU-H71 was well tolerated at the doses administered during this study (10 to 470 mg/m2/day), with no dose limiting toxicities.
KeywordsHsp90 Epichaperome PU-H71 Pharmacokinetics Cancer
This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contracts No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The authors thank Dr. Mariam Konaté, Kelly Services, for editorial support in the preparation of this manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
- 3.Rodina A, Wang T, Yan P, Gomes ED, Dunphy MP, Pillarsetty N, Koren J, Gerecitano JF, Taldone T, Zong H, Caldas-Lopes E, Alpaugh M, Corben A, Riolo M, Beattie B, Pressl C, Peter RI, Xu C, Trondl R, Patel HJ, Shimizu F, Bolaender A, Yang C, Panchal P, Farooq MF, Kishinevsky S, Modi S, Lin O, Chu F, Patil S, Erdjument-Bromage H, Zanzonico P, Hudis C, Studer L, Roboz GJ, Cesarman E, Cerchietti L, Levine R, Melnick A, Larson SM, Lewis JS, Guzman ML, Chiosis G (2016) The epichaperome is an integrated chaperome network that facilitates tumour survival. Nature 538:397–401CrossRefPubMedPubMedCentralGoogle Scholar
- 8.Jhaveri K, Ochiana SO, Dunphy MP, Gerecitano JF, Corben AD, Peter RI, Janjigian YY, Gomes-DaGama EM, Koren J 3rd, Modi S, Chiosis G (2014) Heat shock protein 90 inhibitors in the treatment of cancer: current status and future directions. Expert Opin Investig Drugs 23:611–628CrossRefPubMedPubMedCentralGoogle Scholar
- 14.Whitesell L, Mimnaugh EG, De Costa B, Myers CE, Neckers LM (1994) Inhibition of heat shock protein HSP90-pp60v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation. Proc Natl Acad Sci U S A 91:8324–8328CrossRefPubMedPubMedCentralGoogle Scholar
- 17.Kummar S, Gutierrez ME, Gardner ER, Chen X, Figg WD, Zajac-Kaye M, Chen M, Steinberg SM, Muir CA, Yancey MA, Horneffer YR, Juwara L, Melillo G, Ivy SP, Merino M, Neckers L, Steeg PS, Conley BA, Giaccone G, Doroshow JH, Murgo AJ (2010) Phase I trial of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat shock protein inhibitor, administered twice weekly in patients with advanced malignancies. Eur J Cancer 46:340–347CrossRefPubMedGoogle Scholar
- 18.Ramanathan RK, Egorin MJ, Erlichman C, Remick SC, Ramalingam SS, Naret C, Holleran JL, TenEyck CJ, Ivy SP, Belani CP (2010) Phase I pharmacokinetic and pharmacodynamic study of 17-dimethylaminoethylamino-17-demethoxygeldanamycin, an inhibitor of heat-shock protein 90, in patients with advanced solid tumors. J Clin Oncol 28:1520–1526CrossRefPubMedPubMedCentralGoogle Scholar
- 21.Moulick K, Ahn JH, Zong H, Rodina A, Cerchietti L, Gomes DaGama EM, Caldas-Lopes E, Beebe K, Perna F, Hatzi K, Vu LP, Zhao X, Zatorska D, Taldone T, Smith-Jones P, Alpaugh M, Gross SS, Pillarsetty N, Ku T, Lewis JS, Larson SM, Levine R, Erdjument-Bromage H, Guzman ML, Nimer SD, Melnick A, Neckers L, Chiosis G (2011) Affinity-based proteomics reveal cancer-specific networks coordinated by Hsp90. Nat Chem Biol 7:818–826CrossRefPubMedPubMedCentralGoogle Scholar
- 22.Nayar U, Lu P, Goldstein RL, Vider J, Ballon G, Rodina A, Taldone T, Erdjument-Bromage H, Chomet M, Blasberg R, Melnick A, Cerchietti L, Chiosis G, Wang YL, Cesarman E (2013) Targeting the Hsp90-associated viral oncoproteome in gammaherpesvirus-associated malignancies. Blood 122:2837–2847CrossRefPubMedPubMedCentralGoogle Scholar
- 23.Cerchietti LC, Lopes EC, Yang SN, Hatzi K, Bunting KL, Tsikitas LA, Mallik A, Robles AI, Walling J, Varticovski L, Shaknovich R, Bhalla KN, Chiosis G, Melnick A (2009) A purine scaffold Hsp90 inhibitor destabilizes BCL-6 and has specific antitumor activity in BCL-6-dependent B cell lymphomas. Nat Med 15:1369–1376CrossRefPubMedPubMedCentralGoogle Scholar
- 25.Caldas-Lopes E, Cerchietti L, Ahn JH, Clement CC, Robles AI, Rodina A, Moulick K, Taldone T, Gozman A, Guo Y, Wu N, de Stanchina E, White J, Gross SS, Ma Y, Varticovski L, Melnick A, Chiosis G (2009) Hsp90 inhibitor PU-H71, a multimodal inhibitor of malignancy, induces complete responses in triple-negative breast cancer models. Proc Natl Acad Sci U S A 106:8368–8373CrossRefPubMedPubMedCentralGoogle Scholar
- 27.Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247CrossRefPubMedGoogle Scholar
- 29.Sang J, Acquaviva J, Friedland JC, Smith DL, Sequeira M, Zhang CH, Jiang Q, Xue LQ, Lovly CM, Jimenez JP, Shaw AT, Doebele RC, He SQ, Bates RC, Camidge DR, Morris SW, El-Hariry I, Proia DA (2013) Targeted inhibition of the molecular chaperone Hsp90 overcomes ALK inhibitor resistance in non-small cell lung cancer. Cancer Discov 3:430–443CrossRefPubMedPubMedCentralGoogle Scholar
- 40.Oh WK, Galsky MD, Stadler WM, Srinivas S, Chu F, Bubley G, Goddard J, Dunbar J, Ross RW (2011) Multicenter phase II trial of the heat shock protein 90 inhibitor, retaspimycin hydrochloride (IPI-504), in patients with castration-resistant prostate cancer. Urology 78:626–630CrossRefPubMedPubMedCentralGoogle Scholar
- 42.Goldman JW, Raju RN, Gordon GA, El-Hariry I, Teofilivici F, Vukovic VM, Bradley R, Karol MD, Chen Y, Guo W, Inoue T, Rosen LS (2013) A first in human, safety, pharmacokinetics, and clinical activity phase I study of once weekly administration of the Hsp90 inhibitor ganetespib (STA-9090) in patients with solid malignancies. BMC Cancer 13:152–161CrossRefPubMedPubMedCentralGoogle Scholar
- 43.Jhaveri K, Chandarlapaty S, Lake D, Gilewski T, Robson M, Goldfarb S, Drullinsky P, Sugarman S, Wasserheit-Leiblich C, Fasano J, Moynahan ME, D'Andrea G, Lim K, Reddington L, Haque S, Patil S, Bauman L, Vukovic V, El-Hariry I, Hudis C, Modi S (2014) A phase II open-label study of Ganetespib, a novel heat shock protein 90 inhibitor for patients with metastatic breast cancer. Clin Breast Cancer 14:154–160CrossRefPubMedGoogle Scholar
- 50.Taldone T, Zatorska D, Ochiana SO, Smith-Jones P, Koziorowski J, Dunphy MP, Zanzonico P, Bolaender A, Lewis JS, Larson SM, Chiosis G, Pillarsetty NVK (2016) Radiosynthesis of the iodine-124 labeled Hsp90 inhibitor PU-H71. J Labelled Comp Radiopharm 59:129–132CrossRefPubMedPubMedCentralGoogle Scholar
- 51.Gerecitano JF, Modi S, Rampal R, Drilon AE, Fury MG, Gounder MM, Harding JJ, Hyman DM, Varghese AM, Voss MH, France FO, Taldone T, DaGama EG, Uddin M, Chiosis G, Lewis JS, Lyashchenko SK, Larson SM, Pressl C, Dunphy M (2015) Phase I trial of the HSP-90 inhibitor PU-H71. J Clin Oncol 33:2537–2537CrossRefGoogle Scholar